Radiation Oncology: A Question-Based Review

Hepatocellular Carcinoma

John P. Christodouleas and Salma Jabbour

image Background

What liver Dz is associated with hepatocellular carcinoma (HCC)?

Most HCCs develop in pts with cirrhosis from liver parenchymal Dz. Exposures and Dz that cause chronic hepatitis and cirrhosis are almost uniformly associated with HCC.

HCC is most common in what 2 regions in the world?

Most common regions for HCC:

1.     Asia (East > Southeast)

2.     Africa (middle > East > West)

Name 2 viruses associated with HCC.

Most important viral causes of HCC:

1.     Hepatitis B virus (HBV; carrier state without associated cirrhosis is also a cause)

2.     Hepatitis C virus (HCV)

Name the 2 most important environmental exposures associated with HCC.

Environmental exposures associated with HCC:

1.     Heavy ethanol consumption, which leads to cirrhosis

2.     Aflatoxin B, a mycotoxin that contaminates corn, soybeans, and peanuts, generally in sub-Saharan Africa and East and Southeast Asia

Name 3 hereditary conditions associated with HCC.

Relatively common hereditary conditions associated with HCC:

1.     Hemachromatosis

2.     α1-antitrypsin deficiency

3.     Wilson Dz

Is there a gender predilection for HCC?

Yes. Males are 3 times more likely to develop HCC.

Worldwide, where does HCC rank as a cause of cancer death?

Worldwide, HCC is the 4th leading cause of cancer death (3rd for men), but rates vary dramatically by region.

HCC incidence peaks in what decade of life?

HCC incidence peaks in the 6th decade of life.

What is the most common clinical presentation of HCC?

The most common clinical presentation of HCC is rising AFP in the setting of worsening pre-existing liver Dz.

Who should be screened for HCC and how?

Pts with cirrhosis, hepatitis B carrier state, or nonalcoholic steatohepatitis should be screened for HCC. Screen with AFP and liver US every 6–12 mos.

Do most pts with HCC present with localized or metastatic Dz?

90% of HCC pts present with localized Dz.

In HCC, what are the most common sites of metastatic spread?

HCC most commonly metastasizes to intra-abdominal LNs and lungs. Less common sites of mets include bone, brain, and adrenal glands.

image Workup/Staging

What is the workup of suspected HCC?

Suspected HCC workup: H&P, AFP, CBC, CMP with LDH, LFTs, PT/INR, hepatitis panel (HBV/HCV studies), triphasic CT abdomen or MRI liver, chest imaging, and percutaneous Bx if necessary

For a pt with suspected HCC, when is a Bx unnecessary to establish the Dx?

In HCC, a Bx is not necessary to establish Dx if:

1.     A liver lesion is >2 cm, has classic appearance by 1 imaging modality (CT, US, MRI, angiography), and is associated with AFP > 200 ng/mL

2.     A liver lesion is 1–2 cm and has classic appearance by 2 imaging modalities

Note: If a liver lesion is <1 cm, then the pt should be followed with serial imaging.

In what HCC variant is the AFP level often normal?

AFP levels are normal in the majority of pts with fibrolamellar carcinoma (FLC, a variant of HCC. It is found commonly in females and has a good prognosis. Note that some authors argue that FLC is not truly a variant of HCC since it usually occurs in the absence of cirrhosis.

What are the characteristic triphasic CT and MRI findings of an HCC liver lesion?

1.     On dynamic CT: early phase, tumor is seen as hyperintense b/c of increased vascularity. In the later phase, the tumor is hypodense.

2.     On MRI T1-weighted images: low signal intensity and intermediate signal intensity on T2; HCC appears hypervascular, has increased T2 signal, and shows venous invasion

What is the AJCC 7th edition (2009) TNM staging for HCC?

Note: Bold text highlights 7th edition changes.

1.     T1: solitary tumor without vascular invasion

2.     T2: solitary tumor with vascular invasion or multiple tumors ≤5 cm

3.     T3a: multiple tumors >5 cm

4.     T3b: single tumor or multiple tumors of any size involving major branch of portal or hepatic veins

5.     T4: tumor with direct invasion of adjacent organs other than gallbladder or with perforation of visceral peritoneum

6.     N1: regional LN mets (hilar, hepatoduodenal ligament, inf phrenic LN [no longer classified as M1], and caval LNs)

7.     M1: DMs

What are the AJCC 7th edition (2009) stage groupings for HCC?

Note: Bold text highlights 7th edition changes.

1.     Stage I: T1N0

2.     Stage II: T2N0

3.     Stage IIIA: T3aN0

4.     Stage IIIB: T3bN0

5.     Stage IIIC: T4N0

6.     Stage IVA: TXN1M0

7.     Stage IVB: TXNXM1

Name 3 systems (other than AJCC) used to stage HCC internationally.

Staging systems for HCC commonly used outside the U.S.:

1.     BCLC (Barcelona Clinic Liver Cancer)

2.     CLIP (Cancer of the Liver Italian Program)

3.     JIS score (Japanese Integrated Staging)

Applicability of each of these staging systems appears to depend on the Tx method.

What does a Child-Pugh score predict in pts with chronic liver Dz?

The Child-Pugh score was originally used to estimate operative mortality risk but is currently used to assess OS prognosis for pts with liver failure. Based on cumulative scores, pts are divided into class A, B, or C, with C being the poorest risk.

What are the 5 components of the Child-Pugh score in chronic liver Dz?

Components of the Child-Pugh score include total bilirubin, serum albumin, INR, degree of ascites, and degree of hepatic encephalopathy.

What does the acronym MELD represent, and what does the MELD score predict in chronic liver Dz?

MELD stands for Model for End-Stage Liver Disease, initially developed to predict the 3-mo mortality after a transjugular intrahepatic portosystemic shunt (TIPS) procedure. Now it is used to assess severity of chronic liver Dz and the 3-mo OS without a liver transplant. The MELD score is highly correlated with the Child-Pugh score.

What are the 3 components of the MELD score in chronic liver Dz?

Components of the MELD score include total bilirubin, INR, and Cr.

image Treatment/Prognosis

What 3 features of the HCC pt and the pt's tumors define the appropriate Tx paradigm?

The 3 features that define the Tx options for a pt with HCC are whether the pt (a) has metastatic Dz, (b) has resectable localized tumor, and (c) is medically fit for major surgery.

What are the only 2 curative Tx options for HCC?

The only 2 established curative Tx options for HCC are partial hepatectomy to –margins and liver transplantation. Potentially curative RT Tx with hypofractionated photons and proton therapy are being explored.

Partial hepatectomy is an option in which HCC pts?

Partial hepatectomy is a potentially curative option in HCC pts who are medically fit for surgery, have a solitary mass without major vascular involvement, are Childs-Pugh class A with mild or moderate portal hypertension, and have adequate future liver remnant (if no cirrhosis, require >20% of liver; if Childs A cirrhosis, require >30% of liver). Attempt at curative resection in HCC pts with multifocal tumors and major vascular invasion is controversial.

What % of HCC pts will have an LR after partial hepatectomy after 5 yrs?

~75% of pts with HCC will have an LR (new primary or local spread). (Mathurin P et al., Aliment Pharmacal Ther 2003)

In pts with localized resectable HCC, what adj Tx improves LC and survival after partial hepatectomy?

A study from China found that in pts with HCC s/p partial hepatectomy, adj intra-arterial lipiodol I-131 improved LC and possibly OS (Lau WY et al., Ann Surg 2008). Confirmatory studies are under way.

What criteria are used to determine if liver transplant is an option for a pt with HCC?

The United Network for Organ Sharing (UNOS) criteria are used to determine if liver transplantation is appropriate in a pt with HCC. Per the UNOS criteria, transplantation is an option for medically fit pts with a single tumor ≤5 cm or 2–3 tumors ≤3 cm.

What are the Tx options for an HCC pt with localized Dz who is medically unfit for major surgery?

Tx options for an HCC pt with localized Dz but who is unfit for major surgery:

1.     Sorafenib for Child-Pugh A or B pt

2.     Tumor ablation procedure (radio frequency, cryoablation, microwave, percutaneous alcohol injection)

3.     Tumor embolization procedure (chemoembolization [aka trans-arterial chemoembolization (TACE)], bland embolization, radioembolization)

4.     EBRT, including stereotactic body radiation therapy (SBRT) and proton therapy techniques

In the U.S., what isotope is most commonly used for radioembolization for HCC pts?

In the U.S., the most commonly used isotope for radioembolization in HCC pts is yttrium-90, a pure β-emitter.

What are the 2 forms of microspheres used for radioembolization in HCC pts, and what is the difference between them?

Microspheres used for radioembolization in HCC pts:

1.     TheraSphere (glass microspheres)

2.     SIR-Spheres (resin microspheres)

Estimate the response rate of HCC to yttrium-90–labeled microspheres.

The response rate of HCC to yttrium-90–labeled microspheres varies from 50%–80% depending on the definition of response used.

What are the EB Tx options with either medically inoperable or technically unresectable HCC?

A number of methods of externally irradiating pts with HCC have been explored:

1.     Whole liver RT for palliation (21 Gy in 7 fx)

2.     High-dose RT (>50 Gy) with standard fractionation

3.     Hyperfractionated RT with chemosensitization

4.     Hypofractionated stereotactic RT

5.     Proton therapy

Currently, there is no standard EB technique for unresectable or medically inoperable HCC pts.

What are the Tx options for an HCC pt with metastatic Dz?

The only standard active Tx option for metastatic HCC is sorafenib. HCC typically does not respond to traditional cytotoxic chemo.

What is the MS in metastatic or inoperable HCC pts treated with sorafenib alone?

The MS of metastatic or inoperable HCC pts treated with sorafenib alone is 10.7 mos. (Llovet JM et al., NEJM 2008)

What are the dose and results of SBRT for HCC?

1.     In a phase I study for HCC and cholangiocarcinoma, 41 pts rcv 6 fx SBRT, with the dose delivered depending on the volume of liver irradiated based on the normal tissue complication probability model (24–54 Gy, median 36 Gy). No radiation-induced liver disease (RILD) or grade 4–5 toxicities were seen. Grade 3 liver enzymes were present in 12% of pts. (Tse RV et al., JCO 2008)

2.     Another single institutional experience utilized 12.5 Gy × 3 (<4 cm and no cirrhosis) or 5 Gy × 5 or 10 Gy × 3 (≥4 cm with cirrhosis) with LC rates of 94% and 82% in 1 and 2 yrs, respectively. (Mendez Romero A et al., Acta Oncol 2006)

What is the role for proton beam in the management of unresectable HCC?

A Japanese prospective study enrolled 51 pts with tumors >2 cm from the porta hepatis and GI tract were treated with 66 cobalt Gray equivalents in 10 fx. LC was 94.5% at 3 yrs and 87.8% at 5 yrs. There were minor grade 1 acute adverse events, and only 3 pts were rated higher than grade 2. (Fukumitsu N et al., IJROBP 2009)

image Toxicity

What are the components of the clinical syndrome of RILD?

Signs and Sx of RILD include fatigue, RUQ pain, ascites, anicteric hepatomegaly, and elevated liver enzymes (especially alk phos that occurs 2 wks to 3 mos of the end of RT.

What is the histologic hallmark of RILD?

The pathologic hallmark of RILD is veno-occlusive Dz with venous congestion of the central portion of the liver lobule. Hepatocyte atrophy and fibrosis eventually develop.

What is the Emami RILD TD 5/5 for whole liver RT in 2 Gy/fx?

The Emami RILD TD 5/5 for whole liver RT in 2 Gy/fx is 30 Gy.

What is the Emami RILD TD 50/5 for whole liver RT in 2 Gy/fx?

The Emami RILD TD 50/5 for whole liver RT in 2 Gy/fx is 42 Gy.

What is the RILD TD 5/5 for whole liver RT in 6 fx?

The RILD TD 5/5 for whole liver RT in 6 fx is ~21 Gy.

What is the RILD TD 5/5 for RT to more than one third of the liver in 1.8 Gy/fx?

The RILD TD 5/5 for RT to more than one third of the liver in 1.8 Gy/fx is ~68.4 Gy.